rs201190869

chr12-49041141-G-Achr12-49041141-G-Cchr12-49041141-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_003482.4(KMT2D):c.6629C>T(p.Pro2210Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,525,190 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2210S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (9 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 2.09

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.0038921535).
• BP6: Variant 12-49041141-G-A is Benign according to our data. Variant chr12-49041141-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49041141-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 331 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.6629C>T	p.Pro2210Leu	missense_variant	32/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.6629C>T	p.Pro2210Leu	missense_variant	32/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 152084 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00970

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00260 AC: 443 AN: 170462 Hom.: 1 AF XY: 0.00264 AC XY: 239 AN XY: 90568

Gnomad AFR exome AF: 0.000215

Gnomad AMR exome AF: 0.000915

Gnomad ASJ exome AF: 0.00206

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000695

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.00258

GnomAD4 exome AF: 0.00206 AC: 2824 AN: 1372988 Hom.: 9 Cov.: 35 AF XY: 0.00202 AC XY: 1364 AN XY: 674520

Gnomad4 AFR exome AF: 0.000297

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.00235

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000425

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00196

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152202 Hom.: 2 Cov.: 32 AF XY: 0.00224 AC XY: 167 AN XY: 74410

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00970

Gnomad4 NFE AF: 0.00272

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00136

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00246 AC: 20

ExAC AF: 0.00215 AC: 253

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 06, 2022	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	This variant is associated with the following publications: (PMID: 29569031, 24728327) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KMT2D: BP4, BS1 -

Kabuki syndrome 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 05, 2019	- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	15
Dann	Benign	0.78
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.74	D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.21
Sift	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.077
MVP		0.093
MPC		0.17
ClinPred		0.0042	T
GERP RS		3.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.039
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201190869; hg19: chr12-49434924; COSMIC: COSV56485290; COSMIC: COSV56485290;